Aldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiotoxicity.
Aldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiotoxicity.
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DOI：
10.1038/s41598-017-03284-w
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发表时间：
2017-06-09
影响因子：
4.6
通讯作者：
Srivastava SK
中科院分区：
文献类型：
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作者：
Sonowal H;Pal PB;Wen JJ;Awasthi S;Ramana KV;Srivastava SK
阿霉素 (DOX) 和柔红霉素等蒽环类药物仍然是癌症治疗中最活跃的广谱且最具成本效益的药物。然而，结直肠癌（CRC）细胞对蒽环类药物具有固有的耐药性，较高剂量时会导致心脏毒性。我们最近的研究表明，醛糖还原酶 (AR) 抑制剂（如非达司他）可在体外和体内抑制结直肠癌的生长。在这里，我们证明用 fidarestat 处理 CRC 细胞可增加 DOX 诱导的 HT-29 和 SW480 细胞以及裸鼠异种移植物死亡的功效。 AR 抑制还会导致细胞内 DOX 的积累增加，并降低药物转运蛋白 MDR1、MRP1 和 ABCG2 的表达。此外，fidarestat 还可以抑制 DOX 诱导的血清和心脏中肌钙蛋白-I 和各种炎症标志物的增加，并恢复小鼠的心脏功能。这些结果表明，fidarestat 可用作辅助治疗，以增强 CRC 细胞的 DOX 敏感性并减少 DOX 相关的心脏毒性。
Anthracycline drugs such as doxorubicin (DOX) and daunorubicin remain some of the most active wide-spectrum and cost-effective drugs in cancer therapy. However, colorectal cancer (CRC) cells are inherently resistant to anthracyclines which at higher doses cause cardiotoxicity. Our recent studies indicate that aldose reductase (AR) inhibitors such as fidarestat inhibit CRC growth in vitro and in vivo. Here, we show that treatment of CRC cells with fidarestat increases the efficacy of DOX-induced death in HT-29 and SW480 cells and in nude mice xenografts. AR inhibition also results in higher intracellular accumulation of DOX and decreases the expression of drug transporter proteins MDR1, MRP1, and ABCG2. Further, fidarestat also inhibits DOX–induced increase in troponin-I and various inflammatory markers in the serum and heart and restores cardiac function in mice. These results suggest that fidarestat could be used as adjuvant therapy to enhance DOX sensitivity of CRC cells and to reduce DOX-associated cardiotoxicity.